The present invention relates to a process for producing (2R,3S)-3-amino-4-phenylbutane-1,2-epoxide (hereinafter also referred to as 3-amino-1,2-oxirane), which is useful as an intermediate for the production of an HIV protease inhibitor.
The processes so far known for producing said (2R,3S)-3-amino-1,2-oxirane comprise starting with L-phenylalanine, reducing the carboxyl group thereof to an alcohol function, reoxidizing the same to an aldehyde function, and thereafter 1) directly causing formation of the epoxide using a dimethylsulfonium methylide (J. Org. Chem., 1985, 50, 4615; J. Med. Chem., 1992, 35, 2525), 2) converting the aldehyde to the corresponding olefin by the Wittig reaction and epoxidizing the olefin using m-chloroperbenzoic acid (J. Org. Chem., 1987, 52, 1487; J. Med. Chem. 1992, 35, 1685), 3) reacting the aldehyde with trimethylsilylmethylmagnesium chloride, converting the resulting trimethylsilylalcohol to the corresponding olefin by treatment with trifluoroboron and, as in the method 2) mentioned above, conducting epoxidation using m-chloroperbenzoic acid (EP 0532-466 A2, U.S. Pat. No. 5,514,814) or 4) converting L-phenylalanine to the diazoketone form, degradating the same with hydrochloric acid, reducing the resulting xcex1-ketone with NaBH4 and treating the resulting chlorohydrin with a base to give the epoxide (J. Med. Chem., 1994, 37, 1758), among others.
Meanwhile, there is no precedent technology for producing (2R,3S)-3-amino-1,2-oxirane compounds represented by the general formula (8) starting with a (2S,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutane compound or a (2S,3S)-3-amino-1,2-oxirane compound as in the process of the present invention.
Referring to the above known processes, the process 1) is disadvantageous in that it is necessary to use the sulfur compound in large amounts in the step of epoxide formation, the methods 2) and 3) are disadvantageous in that it is necessary to use the peroxide, which is explosive, in large amounts, and the method 4) is disadvantageous in that it is necessary to handle the diazo compound, which is also explosive, and, in addition, the selectivity toward the desired (2R,3S)-chlorohydrin in NaBH4 reduction is low. Thus, every process comprises a step undesirable from the viewpoint of commercial scale practicing.
In view of the problems mentioned above, the present inventors made intensive investigations in an attempt to develop a process for producing a (2R, 3S)-3-amino-1,2-oxirane compounds which can be carried out efficiently and on a commercial scale and, as a result, succeeded in developing a novel process for production which starts with a (2S, 3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutane compound or a (2S, 3S) -3-amino-1, 2-oxirane compound and involves three steps, namely acyloxylation, sulfonate ester formation and treatment with a base.
Thus, the present invention relates to a process for producing (2R, 3S)-3-amino-4-phenylbutane-1,2-epoxide compounds represented by the general formula (8): 
wherein R1 represents an amino-protecting group, which comprises
treating a (2S, 3S)-3-amino-1-halo-2-hydroxy-4-phenylbutane compound represented by the general formula (1) or a (2S, 3S)-3-amino-4-phenylbutane-1,2-epoxide represented by the general formula (2): 
wherein R1 is as defined above and X represents a halogen atom, 
wherein R1 is as defined above,
with a carboxylic acid quaternary ammonium salt represented by the general formula (3) or a carboxylic acid metal salt represented by the general formula (4):
R3R4R5R6N+OCOR2xe2x88x92xe2x80x83xe2x80x83(3)
xe2x80x83wherein R2 represents an alkyl, aryl or aralkyl group and R3, R4, R5 and R6 may be the same or different and each independently represents an alkyl or aralkyl group,
R2COOxe2x88x92M+xe2x80x83xe2x80x83(4)
xe2x80x83wherein R2 is as defined above and M represents a metal atom, and a quaternary ammonium salt represented by the general formula (5):
xe2x80x83R3R4R5R6Nxe2x80x2Yxe2x88x92xe2x80x83xe2x80x83(5)
xe2x80x83wherein R3, R4, R5 and R6 are as defined above and Y represents a halogen atom, to give a (2S, 3S) -1-acyloxy-3-amino-2-hydroxy-4-phenylbutane compound represented by the general formula (6): 
xe2x80x83wherein R1 and R2 are as defined above,
further treating said (2S, 3S)-1-acyloxy-3-amino-2-hydroxy-4-phenylbutane compound with a sulfonic acid halide in the presence of an organic base
to give a (2S, 3S)-1-acyloxy-3-amino-2-sulfonyloxy-4-phenylbutane compound represented by the general formula (7): 
xe2x80x83wherein R1 and R2 are as defined above and R7 represents an alkyl, aryl or aralkyl group,
and furthermore treating said (2S, 3S)-1-acyloxy-3-amino-2-sulfonyloxy-4-phenylbutane compound with an inorganic base.
The (2S, 3S)-3-amino-1-halo-2-hydroxy-4-phenylbutane compound can be synthesized, for example, by N-protection of L-phenylalanine, which is a naturally-occurring and inexpensive substance, followed by esterification, and stereoselective reduction of the haloketone resulting from chain extension (Japanese Kokai Publication Hei-08-823756).
The starting compound in the present process is the above-mentioned (2S, 3S)-3-amino-1-halo-2-hydroxy-4-phenylbutane compound of the general formula (1) or (2S, 3S)-3-amino-4-phenylbutane-1,2-epoxide compound of the general formula (2). In the formulas, R1 represents an amino-protecting group in common use, such as a methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl, acetyl, benzoyl or chloroacetyl group, desirably a t-butoxycarbonyl or benzyloxycarbonyl group, and X represents a halogen atom such as a chlorine or bromine atom.
The acyloxylating agent to be used in the above process is the above-mentioned carboxylic acid quaternary ammonium salt of the general formula (3), or the carboxylic acid metal salt of the general formula (4) plus the quaternary ammonium salt of the general formula (5). In the formula (3), R2 represents an alkyl, aryl or aralkyl group. The alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl. The aryl group is, for example, phenyl or tolyl. The aralkyl group is, for example, benzyl. A methyl group is preferred as R2, however. In the formula (3), M specifically includes, among others, lithium, sodium, potassium, magnesium and calcium, and is preferably sodium or potassium. R3, R4, R5 and R6 each independently represents an alkyl or aralkyl group. The alkyl group includes, among others, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl. The aralkyl group is, for example, benzyl. Among these, butyl is preferred. Y is a halogen atom, such as a chlorine or bromine atom.
In the general formula (7) representing the sulfonate ester, R7 represents an alkyl, aryl or aralkyl group. The alkyl group is, for example, methyl or ethyl. The aryl group is, for example, phenyl, p-methylphenyl or p-nitrophenyl. The aralkyl group is, for example, benzyl. Among them, methyl is preferred.
In accordance with the present invention, the above (2S, 3S)-1-acyloxy-3-amino-2-sulfonyloxy-4-phenylbutane compound (6) is first derived from the (2S, 3S)-3-amino-1-halo-2-hydroxy-4-phenylbutane compound (1) or (2S, 3S)-3-amino-1, 2-oxirane compound (2) by treatment with the carboxylic acid quaternary ammonium salt (3), for example tetrabutylammonium acetate, or with the carboxylic acid metal salt (4) and quaternary ammonium salt (5), for example calcium acetate or sodium acetate, and tetrabutylammonium chloride or tetrabutylammonium bromide.
The solvent to be used in the above step is not particularly restricted but includes, among others, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane and toluene. Among them, acetone, acetonitrile and N,N-dimethylformamide are preferred.
The carboxylic acid quaternary ammonium salt (3) is used generally in an amount of 1.0 to 2.0 moles, preferably 1.2 moles, per mole of the compound (1) or (2). The carboxylic acid metal salt (4) and quaternary ammonium salt (5) are used generally in a molar ratio of (1) or (2)/carboxylic acid metal salt/quaternary ammonium salt=1.0 mole/1.0 to 5.0 moles/0.05 to 2.0 moles, preferably 1.0 mole/2.0 moles/0.05 mole.
The reaction is carried out generally at a temperature of 60xc2x0 C. to 100xc2x0 C., preferably 60xc2x0 C. to 80xc2x0 C. The reaction time is generally 5 to 24 hours, preferably about 10 to 12 hours, although it may vary depending on the reaction temperature.
After the reaction, the (2S, 3S)-1-acyloxy-3-amino-2-hydroxy-4-phenylbutane compound (6) formed can be recovered by extraction with a solvent such as ethyl acetate and can be further purified by such techniques as column chromatography and/or recrystallization.
The sulfonic acid esterification of the (2S, 3S)-1-acyloxy-3-amino-2-hydroxy-4-phenylbutane compound (6) is carried out in the presence of an organic base by using 1.0 to 3 moles of a sulfonic acid halide per mole of the compound (6). The sulfonic acid halide includes, among others, sulfonyl chlorides, specifically methanesulfonyl chloride, toluene-sulfonyl chloride and the like. As the organic base, there may be mentioned tertiary-amines, specifically pyridine, triethylamine, tripropylamine, methyldiisopropylamine, ethyldiisopropylamine, N,N-dimethylaniline and the like. Among them, pyridine and triethylamine are preferred. Any solvent not inhibiting the reaction may be used without any particular restriction. Thus, for example, toluene, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, methylene chloride and chloroform may be mentioned. The organic base mentioned above may be used singly as such.
The base is used generally in an amount of 1.0 to 50 moles per mole of the compound (6). The reaction temperature is generally 0xc2x0 C. to 60xc2x0 C., preferably 0xc2x0 C. to 25xc2x0 C. The reaction time is generally 1 to 48 hours, desirably about 20 to 48 hours, although it may vary depending on the amounts of the sulfonic acid halide and base used.
The thus-formed sulfonate ester (7) can be recovered by neutralizing the base by addition of a mineral acid such as hydrochloric acid, followed by extraction with an organic solvent such as ethyl acetate. It can be further purified by such techniques as column chromatography and/or recrystallization.
The epoxidation step is conducted in the presence of an inorganic base. Useful as the inorganic base are, for example, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium acetate and potassium acetate. Potassium carbonate is preferred, however. The inorganic base is used generally in an amount of 0.05 to 5.0 moles, preferably 0.5 to 2.0 moles, per mole of the compound (7). Usable as the solvent are methanol plus an organic solvent such as toluene, tetrahydrofuran, diethyl ether, dioxane or t-butyl methyl ether. Methanol may be used alone. A mixed solvent composed of methanol and THF (1:1 by volume) is preferred. The reaction temperature is generally 0xc2x0 C. to 60xc2x0 C., preferably 25 xc2x0 C. to 30xc2x0 C. The reaction time is generally 1 to 24 hours, preferably 6 to 12 hours.